Targeted therapy by monoclonal antibody (MAb) was an old and simple concept, yet it took a combination of a variety of technologies, including antibody engineering, cell line enhancement, production, purification, formulation, and different QC assay methods to realize the long awaited clinical and therapeutic promises of the “magic bullet.” To date, there are hundreds, if not thousands, of therapeutic MAbs in different stages of clinical trials against a plethora of disease indications. Along with it comes a whole host of different ideas, technologies and know how based on, or derived from MAbs with the hope of expanding the scope of their applications.
One of its ramifications is based on Network Theory, which was proposed by Niels Jerne in 1974 (Jerne N K: Towards a network theory of the immune system. Ann Immunol (Paris) 1974, 125C:373-389). Jerne suggested that the immune system is a network of interacting idiotypes that is involved in the regulation of immune responses. The concept was later evolved into the development of anti-iditotypic antibodies for different applications. Anti-idiotypic antibodies, commonly referred to as Ab2, are those antibodies raised against the immunizing antibodies (Ab1), and demonstrated specific binding against the idiotopes (unique antigenic determinants on the surface of the antibodies) of Ab1. Ab2 can be classified into three distinct groups: (1) Ab2α antibodies are those that recognize idiotopes distinct from the antigen-binding site (ABS) on primary Ab1 antibodies; (2) Ab2β antibodies recognize epitopes within the ABS and mimic the structure, and forming the so-called “internal image,” of the nominal antigen; (3) Ab2γ antibodies recognize epitopes within the ABS without the structural resemblance of the nominal antigen (Pan et al. 1995. Anti-idiotypic antibodies: biological function and structural studies. Faseb J 9:43-49).
Although Ab2β antibodies appear to be the most intriguing group of Ab2 antibodies, especially attempts to use Ab2β as surrogate antigens for the development of active vaccines against autologous and/or inert antigens such as tumor-specific or tumor associated antigens, in addition to bacterial, viral and parasitic infections (Chatterjee et al. 2001. The anti-idiotype vaccines for immunotherapy. Curr Opin Mol Ther 3(1):63-69), development of other types of Ab2 can be useful in developing assay methods that facilitate the production process and clinical evaluation of a potentially therapeutic Ab1.
SM03 is a chimeric anti-CD22 antibody derived from the murine RFB4 antibody (Yang et al. 2006. Construction and characterization of recombinant anti-B-lymphoma chimeric antibody. Chinese J New Drugs 15(3):186-192), and is being used in clinical trials for the treatment of non-Hodgkin's lymphoma (NHL) (Li et al. 2012. Pharmacokinetics and tolerability of human mouse chimeric anti-CD22 MAb in Chinese patients with CD22-positive non-Hodgkin's lymphoma. Landes Bioscience J 4(2):256-266). Since SM03 targets and suppresses matured B cells, the antibody has expanded its indications for the treatment of other autoimmune diseases, such as, among others, Rheumatoid arthritis (RA) and Systemic Lupus Erythamatosus (SLE).
In order to improve the utility of “the anti-CD22 antibody,” SM03 was humanized using the technology of framework-patching (Liang et al. 2006. Framework-reengineering and its application in humanized antibody fSM03. Chinese J New Drugs 15(21):1832-1836; Leung, S. O. Reducing Immunogenicities of Immunoglobulins by Framework-patching. U.S. Pat. No. 7,338,659 B2; Leung, S. O. Framework-patched Immunoglobulins. U.S. Pat. No. 7,321,026 B2). The framework-patched SM03 was later renamed as SM06. Both SM03 and SM06 target the same epitope of the human CD22 antigen, with comparable affinity. However, in terms of sequence and structure, the only thing SM03 and SM06 share in common is their ABSs, formed by their respective complementarily determining region (CDR) sequences.
SM03 and SM06 bind to human CD22 antigen. The antigen is expressed on the surface of matured B cells (Schwartz-Albiez et al. 1991. CD22 antigen: biosynthesis, glycosylation and surface expression of a B lymphocyte protein involved in B cell activation and adhesion. Int Immunol 3:623-633; Stoddart et al. 1997. Analysis of murine CD22 during B cell development: CD22 is expressed on B cell progenitors prior to IgM. Int Immunol 9:1571-1579), and upon binding to the antigen, the antibody-antigen complex is rapidly internalized (Yang et al. 2006; Liang et al. 2006). This has made the development of a biological assay to evaluate the bioactivities of SM03 and SM06 difficult. The same problem applies to other antibodies that target internalizing antigens, such as invariant chain, CD33, Lewis Y antigen, etc. Moreover, convenient and robust methods in evaluating the level of circulating SM03 and SM06 (as well as RFB4) and their derivatives (scoff, Fab, diabodies, immunotoxins, drug conjugates, etc.) are needed for the evaluation of serum half-lives for these products during pharmacokinetic studies. Since soluble CD22 is not widely available, and exogenous CD22 tends to be less stable, the availability of an anti-idiotype antibody against SM03 and its derivatives will be extremely useful for such purposes.
The present invention is therefore directed to the use of anti-idiotypes in immunotherapy trials as diagnostic reagents for monitoring the pharmacokinetics (PK) of the administered antibody in the circulation of patients. The anti-idiotype antibody can similarly be used as a positive control for HAHA, HACA or HAMA immune responses to the administered antibody. Monitoring the presence of such immune responses will influence treatment options as such immune responses may affect the clinical outcome in patients (Gruber, van Haarlem et al. 2000. The human anti-mouse immunoglobulin response and the anti-idiotypic network have no influence on clinical outcome in patients with minimal residual colorectal cancer treated with monoclonal antibody CO17-1A. Cancer Res. 60:1921-1926), or can be associated with undesirable hypersensitive reactions and dramatic changes in PK and biodistribution of the administered antibody.
Another embodiment of the present invention is to provide a general method for the evaluation of biological functions of antibodies that target internalizing antigens, including, CD22, Invariant Chain (CD74), CD33, Lewis Y antigen, etc. The method includes the construction of an engineered cell line that expresses on their surface a non-internalizing fusion protein containing the anti-idiotype binding moiety. In the present invention, the cell line that expresses surface anti-SM03 anti-idiotype antibody (or antibody fragment fusion) can be used for the evaluation of the biologic activity of SM03 and SM06 via complement-dependent cytotoxicity (CDC) or antibody directed cell cytotoxicity (ADCC) as a quality control measure.